Polyphenols and cardiovascular disease: effects on endothelial and
platelet function1– 4
Joseph A Vita
ABSTRACT
Epidemiologic studies suggest that higher polyphenol intake from
fruits and vegetables is associated with decreased risk for cardio-
vascular disease. The mechanisms explaining this observation re-
main unclear. This review summarizes data suggesting that fla-
vonoids improve endothelial function and inhibit platelet
aggregation in humans. The vascular endothelium is a critical reg-
ulator of vascular homeostasis, and endothelial dysfunction contrib-
utes to the pathogenesis and clinical expression of coronary artery
disease. Platelet aggregation is a central mechanism in the patho-
genesis of acute coronary syndromes, including myocardial infarc-
tion and unstable angina. For these reasons, the observed effects of
flavonoids on endothelial and platelet function might explain, in
part, the observed beneficial effects of flavonoids on cardiovascular
disease risk. Am J Clin Nutr 2005;81(suppl):292S–7S.
KEY WORDS Polyphenols, cardiovascular disease, endothe-
lium, platelets, flavonoids, tea
INTRODUCTION
This review represents a summary of a presentation I made at
the 1st International Conference on Polyphenols and Health, in
Vichy, France, on November 20, 2003. The review provides an
overview of epidemiologic data supporting a relationship be-
tween higher intake of polyphenolic flavonoids and reduced risk
of cardiovascular disease. The remainder of the review focuses
on possible mechanisms for this beneficial effect, including im-
proved endothelial function and reduced platelet aggregation.
EPIDEMIOLOGIC STUDIES OF FLAVONOID
CONSUMPTION
Many epidemiologic studies have investigated the relation-
ship between flavonoid intake and cardiovascular disease risk,
and they have provided mixed results (1–12). The subject has
been reviewed (13–17); overall, the evidence suggests that indi-
viduals with the highest flavonoid intake have modestly reduced
risks for cardiovascular disease (1, 3, 4, 7–9). In some studies, the
apparent benefit of flavonoids was quite large. For example, in a
prospective cohort study, Hertog et al (1) used a dietary ques-
tionnaire to assess flavonoid consumption among 805 elderly
men from the Zutphen Elderly Study. The primary dietary
sources of flavonoids in that study were tea, apples, and onions.
The tertile of subjects consuming the greatest amount of fla-
vonoids (쏜 29 mg/d) had a 68% lower cardiovascular risk, after
292S Am J Clin Nutr 2005;81(suppl):292S–7S. Printed in USA. © 2005 American Society for Clinical Nutrition
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adjustment for known cardiovascular risk factors, compared with
individuals in the lowest tertile.
Case-control studies also suggest that high flavonoid intake is
beneficial. For example, Sesso et al (8) examined the relationship
between tea and coffee consumption and myocardial infarction.
A total of 340 subjects with well-documented myocardial infarc-
tion and 340 matched control subjects from the Boston Area
Health Study provided dietary information. The investigators
observed that individuals who drank more than one cup of tea per
day had a 44% reduction in cardiovascular risk. In contrast,
coffee consumption was not significantly associated with de-
creased or increased cardiovascular disease.
Additional support for a benefit of higher flavonoid intake is
provided by studies relating red wine consumption to cardiovas-
cular risk. There is extensive evidence that individuals who con-
sume 1 or 2 drinks per day have reduced cardiovascular risk,
compared with nondrinkers, and much of this benefit has been
attributed to the direct effects of alcohol. However, there is ev-
idence that red wine drinkers have additional benefit, and this
observation has been interpreted to support a benefit of red wine
polyphenols (18 –20).
In addition to apparent benefits of flavonoid intake in the
setting of primary prevention, one recent study suggested that
flavonoid intake in the form of tea might have benefit among
individuals with established cardiovascular disease. Mukamal et
al (10) examined tea consumption in the Myocardial Infarction
Onset Study, a prospective cohort study that examined 1900
patients admitted to community hospitals in the United States
with acute myocardial infarction. During a follow-up period of
3.8 y, moderate and heavy tea drinkers had 31% and 39% reduc-
tions in cardiovascular risk, respectively, after adjustment for
other risk factors.
In contrast to these studies suggesting a benefit, several studies
demonstrated no relationship between flavonoid intake and car-
diovascular risk (2, 5, 6, 12). It is notable that several of these
neutral studies were performed in the United Kingdom, where tea
consumption is relatively high (2, 6). Studies with relatively
1
From Evans Department of Medicine and Whitaker Cardiovascular In-
stitute, Boston University School of Medicine, Boston.
2
Presented at the 1st International Conference on Polyphenols and Health,
held in Vichy, France, November 18 –21, 2004.
3
Supported by NIH grants PO1HL60886, HL52936, and HL75795 and by
North America Tea Trade Health Research Association and DSM Nutritional
Products, Inc.
4
Address correspondence to JA Vita, Section of Cardiology, Boston Medical
Center, 88 East Newton Street, Boston, MA 02118. E-mail: jvita@bu.edu.
 POLYPHENOLS AND CARDIOVASCULAR DISEASE
well-nourished populations, such as US health professionals or
college alumni, also tended to show less benefit of flavonoids (5,
12). In those studies, it is possible that confounding factors
masked benefits of flavonoid consumption. For example, tea
consumption is more common among individuals of low socio-
economic status in the United Kingdom, and such individuals are
known to have increased risk for cardiovascular disease. Fur-
thermore, baseline flavonoid intake may affect the results. If the
population has a relatively high level of flavonoid consumption,
then even subjects in the lowest quartile of consumption may be
receiving the maximal benefits of flavonoid intake. This might
provide an explanation for the lack of effect of tea observed in the
United Kingdom, where consumption is high.
Overall, the evidence does suggest that higher consumption of
flavonoids is associated with modest reduction of cardiovascular
risk, despite the negative results of some studies. For tea, this
conclusion is supported by a meta-analysis by Peters et al (17),
which suggested an overall reduction in cardiovascular disease
risk of 앑11% with consumption of 3 cups of tea per day. A
growing body of work has provided mechanistic information
about how polyphenols might reduce cardiovascular disease,
which provides additional support for a biological effect of poly-
phenols, rather than a simple association of polyphenol intake
with a healthier lifestyle or other confounding factors.
PATHOGENESIS OF CARDIOVASCULAR DISEASE
EVENTS
When considering how polyphenols might reduce cardiovas-
cular risk, it is important to consider recent insights into the
pathogenesis of atherosclerotic cardiovascular disease. Athero-
sclerosis is a chronic inflammatory disease that develops in
lesion-prone regions of medium-sized arteries (21). Atheroscle-
rotic lesions may be present and clinically silent for decades
before becoming active and producing clinical events such as
acute myocardial infarction, unstable angina, or sudden cardiac
death. Such events are often caused by acute rupture or erosion of
a vulnerable plaque, which exposes the highly thrombogenic
subendothelium to flowing blood. The result is acute, platelet-
rich, mural thrombosis that occludes or partially occludes the
arterial lumen to produce infarction or ischemia. The precise
mechanisms accounting for plaque vulnerability and rupture re-
main incompletely understood, but the available data suggest
that local inflammation within the plaque, thinning of the fibrous
cap, and accumulation of plaque lipid may contribute (22). Once
plaque rupture occurs, the extent of thrombosis formation
and acute changes in vascular tone may determine the extent of
ischemia/infarction.
The development of a vulnerable plaque and the subsequent
ischemic events represent a profound loss of vascular homeosta-
sis. Recent studies focusing on vascular biological features pro-
vide a fruitful approach for development of novel treatments and
prevention strategies for cardiovascular disease. In particular,
there is great interest in antithrombotic therapies and therapies
that influence the function of endothelial cells, which are key
regulatory cells in the vessel wall. Relevant to the current review,
there is increasing evidence that flavonoids may have beneficial
effects on endothelial control of thrombosis, inflammation, and
vascular tone. Flavonoids also have beneficial effects on plate-
lets, which occlude the arterial lumen in the setting of acute
coronary syndromes.
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293S
ENDOTHELIAL FUNCTION AND CARDIOVASCULAR
RISK
The vascular endothelium plays a key role in the regulation of
vascular homeostasis, and increasing evidence suggests that al-
terations in endothelial function contribute to the pathogenesis
and clinical expression of cardiovascular disease (23). Endothe-
lial cells regulate vascular homeostasis by producing factors that
act locally in the vessel wall and lumen, and a key endothelial
product is nitric oxide (24). Nitric oxide was first described as an
endothelium-derived vasodilator, but it is now clear that nitric
oxide regulates other important aspects of vascular homeostasis
(25). For example, nitric oxide prevents adherence of leukocytes
to the endothelial surface and inhibits expression of leukocyte
adhesion molecules at the endothelial surface. Nitric oxide pre-
vents platelet adhesion and platelet aggregation. Nitric oxide also
inhibits vascular smooth muscle cell proliferation and alters ex-
pression of noncellular components that constitute the matrix of
the vascular wall, making nitric oxide relevant to lesion forma-
tion, hypertrophy of the vessel wall, and vascular compliance.
Therefore, endothelium-derived nitric oxide has important va-
sodilator, antiinflammatory, antithrombotic, and growth-
suppressing properties that are relevant to all stages of athero-
sclerosis (23).
Other endothelium-derived products regulate vascular ho-
meostasis, including other substances that influence vascular
tone (eg, prostacyclin and endothelin), fibrinolytic factors (tissue
plasminogen activator and plasminogen activator inhibitor-1),
factors that affect coagulation (tissue factor, heparans, and von
Willebrand factor), and proinflammatory factors (eg, adhesion
molecules and inflammatory cytokines) (26). In general, loss of
nitric oxide is paralleled by changes in these other regulatory
mechanisms, leading to the development of a pathologic endo-
thelial phenotype. These observations suggest that the state of the
endothelium may be an indicator of vascular health and that
examining endothelial vasomotor function may have clinical
utility (23).
A common feature of otherwise diverse cardiovascular dis-
ease risk factors is their adverse effects on the endothelium. In
this regard, dyslipidemia, hypertension, diabetes mellitus, smok-
ing, aging, physical inactivity, systemic inflammation and infec-
tious processes, hyperhomocysteinemia, and the postmeno-
pausal state are all associated with endothelial dysfunction.
Genetic and environmental factors might influence the effects of
risk factors on endothelial function. Genetic variation in the
activity of antioxidant enzymes or nitric oxide synthase might
influence the effects of risk factors on endothelial function (27).
Diet might also influence the effects of risk factors on endothelial
function; therefore, polyphenol intake could be important in de-
termining the risk for cardiovascular disease events.
Prospective studies have shown that endothelial dysfunction is
associated with an increased risk of cardiovascular events (28 –
38). One study suggested that improved endothelial function
after treatment of hypertension was associated with improved
outcomes (35). Many interventions known to reduce cardio-
vascular disease risk have the ability to reverse endothelial
dysfunction. For example, lipid-lowering therapy, angiotensin-
converting enzyme inhibitors, angiotensin receptor blockers,
smoking cessation, and exercise have all been shown to reverse
endothelial dysfunction among patients with atherosclerosis or
 294S VITA

cardiovascular risk factors (26). These findings suggest that en- endothelial function. Tea contains an assortment of water-
dothelial function may have utility as a surrogate marker of soluble antioxidant flavonoids, including catechins, quercetin,
cardiovascular risk. Furthermore, endothelial function has kaempferol, and other polyphenols, particularly thearubigins.
evolved into a clinically useful endpoint for studies of potential We examined the short-term and long-term effects of tea con-
interventions for the prevention or treatment of cardiovascular sumption on flow-mediated dilation in the brachial artery among
disease (23). 50 subjects with angiographically proven coronary artery dis-
ease, in a placebo-controlled, crossover study (51). Subjects tak-
ing antioxidant supplements were excluded, and subjects were
STUDIES OF ANTIOXIDANTS AND ENDOTHELIAL asked to refrain from drinking tea and red wine during the study.
DYSFUNCTION All subjects were receiving prescribed medications for coronary
artery disease, and 77% were undergoing lipid-lowering therapy.
With respect to the mechanism of endothelial dysfunction,
Short-term effects of tea were examined by measuring flow-
there has recently been great interest in the importance of oxi-
mediated dilation before and 2 h after the subjects consumed 450
dative stress. These studies fit well with the recognition that
mL of freshly brewed black tea. Long-term effects were exam-
oxidative stress contributes to atherogenesis (39). The impor-
ined by measuring flow-mediated dilation again after the sub-
tance of oxidative stress as a cause of endothelial dysfunction has
jects had consumed 900 mL of black tea per day for 30 d. The
prompted many investigations into the effects of antioxidants on
study used water as a control beverage, and the beverage order
endothelial function. For ascorbic acid in particular, there is
was randomized.
extensive evidence that acute treatment reverses endothelial
Both short-term and long-term tea consumption improved en-
dysfunction in many disease states, including atherosclerosis,
dothelial function, whereas water consumption had no effect.
diabetes mellitus, hypertension, congestive heart failure, renal
There also were no effects of tea consumption on nitroglycerin-
failure, hyperhomocysteinemia, hypercholesterolemia, and
mediated dilation, baseline arterial diameter, or the extent of
others (40).
reactive hyperemia, which confirmed that tea consumption af-
Gokce et al (41) examined the effect of ascorbic acid on bra-
fected endothelial function, rather than the function of vascular
chial artery flow-mediated dilation in a randomized, placebo-
smooth muscle or the stimulus for dilation. Flow-mediated dila-
controlled, double-blind study of patients with coronary artery
tion was not affected by an acute dose of caffeine, which sug-
disease. Flow-mediated dilation reflects shear stress-mediated
gested that the caffeine content of tea did not account for the
nitric oxide production by the endothelium (42). This physiolog-
results. Blood pressure, serum glucose concentrations, and se-
ically relevant response is impaired in the setting of coronary risk
rum lipid concentrations remained stable during tea consump-
factors and is correlated with abnormal responses in the coronary
tion. Although catechins represent a relatively minor component
circulation (43); abnormal responses in the brachial artery pre-
of black tea, they are measurable in plasma. Our study demon-
dict future cardiovascular disease events among high- and low-
strated that total catechin amounts were increased 앑20% after tea
risk patients (34 –36, 38). In the study by Gokce et al (41), bra-
consumption; however, there was no relationship between
chial artery flow-mediated dilation was impaired at baseline.
changes in total catechin amounts and improvements in endo-
Flow-mediated dilation improved 2 h after an acute 2-g dose of
thelial function.
ascorbic acid, and the effect was sustained after 30 d of treatment
Although tea contains flavonoid antioxidants, it remains un-
with 500 mg/d. The responses were unchanged after acute and
clear whether an antioxidant effect explains the observed bene-
chronic treatment with placebo. Mechanistic in vitro studies sug-
fits of tea. Our study demonstrated no effect of tea consumption
gested that the benefit of ascorbic acid may be attributable, in
on plasma antioxidant capacity (51). There also was no effect on
part, to increased activity of nitric oxide synthase resulting from
plasma concentrations of F2-isoprostanes, markers of systemic
stabilization of tetrahydrobiopterin, an essential cofactor for en-
lipid peroxidation, or 8-hydroxydeoxyguanosine, a marker of
zyme activity (44).
DNA oxidation. These findings are consistent with several other
Other water-soluble antioxidant compounds have beneficial
well-conducted studies that failed to demonstrate a reduction in
effects on endothelial function among patients with cardiovas-
markers of oxidative stress after tea consumption (52).
cular disease, including N-acetylcysteine (45, 46), glutathione
Several other studies demonstrated that flavonoid-containing
(47), and the cysteine donor L-2-oxothiazolidine-4-carboxylic
beverages have beneficial effects on endothelial function. For
acid (48). In contrast, the effects of lipid-soluble antioxidants on
example, Hodgson et al (53) examined the effect of tea consump-
endothelium-dependent dilation among human subjects with
tion on brachial artery flow-mediated dilation among a group of
atherosclerosis and cardiovascular risk factors have been rela-
otherwise healthy subjects with modest hypercholesterolemia.
tively disappointing, although benefits have been reported for
Those investigators observed that consumption of 5 cups of black
select, high-risk groups, including patients with type 1 diabetes
tea per day for 5 wk led to improved flow-mediated dilation.
mellitus (49) or multiple risk factors (50).
Interestingly, tea consumption was also associated with an im-
provement in nitroglycerin-mediated dilation, which suggested
that tea improved the bioactivity of endothelium-derived nitric
EFFECTS OF POLYPHENOLS ON ENDOTHELIAL oxide and/or had a beneficial effect on the function of vascular
FUNCTION smooth muscle.
The extensive prior work demonstrating a beneficial effect of Other flavonoid-containing beverages, particularly grape
ascorbic acid on endothelial function prompted us to consider products, have been shown to improve endothelial function.
that other water-soluble antioxidants, such as flavonoids, might Stein et al (54) observed that consumption of grape juice for 14 d
have beneficial effects on endothelial function. To explore this was associated with improved brachial artery flow-mediated di-
possibility, we investigated the effects of tea consumption on lation among 15 adults with angiographically proven coronary

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 POLYPHENOLS AND CARDIOVASCULAR DISEASE
artery disease. In that study, the susceptibility of LDL to ex vivo
oxidation was reduced, which suggested an antioxidant effect. A
second study from the same group also indicated beneficial ef-
fects of purple grape juice on endothelial function (55).
Agewall et al (56) observed an improvement in brachial artery
flow-mediated dilation 쏝 1 h after consumption of dealcohol-
ized red wine among healthy volunteers. In that study, consump-
tion of wine (containing alcohol) was associated with vasodila-
tion and increased blood flow but no observable increase in
flow-mediated dilation. However, the effects of wine on baseline
diameter and flow might have obscured an effect on endothelial
function.
In a recent study, Heiss et al (57) examined the effects of cocoa
on flow-mediated dilation. Among patients with at least one
cardiovascular disease risk factor, impaired endothelial function
was observed. Two hours after the patients consumed cocoa
containing 176 mg/dL flavan-3-ols, the investigators observed a
significant increase in flow-mediated dilation. They also ob-
served increases in nitrosylated and nitrosated species in plasma,
which suggested an increase in nitric oxide production.
POLYPHENOLS AND PLATELET FUNCTION
Platelet aggregation plays a critical role in the pathogenesis of
acute coronary syndromes, and there is extensive evidence that
antiplatelet therapy reduces cardiovascular disease risk (58). An
effect of polyphenols to reduce platelet activity could have a
large impact on cardiovascular disease and might provide an
important mechanistic explanation for the available epidemio-
logic data regarding polyphenols and cardiovascular disease.
Several basic studies demonstrated that flavonoids inhibit
platelet aggregation (59, 60). Purple grape juice inhibited ex vivo
platelet aggregation in whole blood (60). The direct clinical rel-
evance of ex vivo platelet studies is unclear, and an important
study by Demrow et al (59) examined the effects of grape juice
on platelet function in vivo. Those investigators used the Folts
model of unstable coronary stenosis, which involves the creation
of endothelial injury and subocclusive stenosis in a dog coronary
artery. In this model, transient platelet aggregation and release
are reflected in cyclic variations in coronary blood flow; there-
fore, the model closely mimics a ruptured atherosclerotic plaque
causing unstable angina. In this model, acute intragastric admin-
istration of red wine or grape juice was associated with marked
reductions in cyclic flow variations, which indicates an impor-
tant antiplatelet effect that is relevant to cardiovascular disease
events (59).
Regarding the potential mechanisms of flavonoids on platelet
function, Freedman et al (60) examined the effects of grape juice
on platelet function. They observed that addition of grape juice to
platelets ex vivo was associated with a reduction in platelet ag-
gregation, a decrease in platelet production of superoxide anion,
and an increase in platelet nitric oxide production. The beneficial
effects appeared to be related to reduced activation of protein
kinase C. Importantly, these findings were reproduced when the
studies were repeated with platelets isolated from healthy vol-
unteers who had consumed grape juice for 2 wk.
There are mixed data regarding the effects of tea consumption
on platelet function. Animal studies of the effects of tea con-
sumption on platelet aggregation in the Folts model suggested
that tea may have benefits comparable to those of grape juice,
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295S
although rather high doses of tea were required (JD Folts, per-
sonal communication, 2004). We examined the effects of short-
term and long-term tea consumption on ex vivo platelet aggre-
gation in response to ADP or thrombin-related activated peptide
among patients with coronary artery disease (61). That study
demonstrated no effect of tea consumption on platelet function,
although the concurrent aspirin treatment could have influenced
the results. Hodgson et al (62) observed that tea consumption
reduced plasma concentrations of P-selectin, a marker of in vivo
platelet aggregation. It is clear that additional studies will be
required to define the effects of tea on platelet function.
OTHER POLYPHENOLIC COMPOUNDS AND OTHER
POTENTIAL MECHANISMS
Many other polyphenolic compounds have been reported to
reduce cardiovascular disease risk and to have beneficial effects
on endothelial and platelet function; a detailed discussion of
these compounds is beyond the scope of the present review. For
example, soy products, which are rich sources of isoflavones
such as genistein and daidzein, have been reported to improve
endothelial function, possibly through an effect on the ␣ estrogen
receptor (63).
There is great interest currently in the importance of systemic
inflammation as a pathogenic mechanism of cardiovascular risk
(64). Importantly, there is growing evidence that polyphenolic
compounds may have antiinflammatory effects. For example,
the grape and wine component resveratrol inhibits adhesion mol-
ecule expression and monocyte adhesion in vitro (65). Addi-
tional study of the antiinflammatory effects of polyphenols is
clearly warranted.
CONCLUSIONS
This article has reviewed epidemiologic and mechanistic stud-
ies that suggest that polyphenols have beneficial effects on the
cardiovascular system and reduce the risk of cardiovascular dis-
ease. It should be emphasized that some of the epidemiologic
data are conflicting, and this review considered some possible
explanations for the reported negative findings for certain well-
nourished populations and populations with high flavonoid in-
take overall. Improved endothelial function, antiplatelet effects,
and antiinflammatory effects are among the important mecha-
nisms to be considered for the observed benefits. Overall, the
findings of available studies fit well with the recommendations of
the American Heart Association that Americans should increase
their consumption of fruits and vegetables and other foods with
high polyphenol contents (66).
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